The AIDS epidemic is one of the most challenging problems in medicine in the 21st century. A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a vitally encoded protease to generate mature vital proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. It has been previously demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
Among many strategies to combat this disease, highly active antiretroviral therapy (HAART) with HIV protease inhibitors (PIs) in combination with reverse transcriptase inhibitors (RTIs) continues to be the first line treatment for control of HIV infection. This treatment regimen has definitely improved quality of life, enhanced HIV management, and halted the progression of the disease. However, despite these impressive successes, there remain many challenges to treating this devastating disease, including decreasing both the toxicity of and complexity of these treatment regimens. In addition, there is a growing population of patients that are developing multi-drug resistant strains of HIV, and there is ample evidence that these strains can be further transmitted.
HAART has had a major impact on the AIDS epidemic in industrially advanced nations; however, eradication of human immunodeficiency virus type 1 (HIV 1) appears to be currently unachieved, in part due to the viral reservoirs remaining in blood and infected tissues. The limitation of antiviral therapy of AIDS is also exacerbated by complicated regimens, the development of drug-resistant HIV-1 variants, and a number of inherent adverse effects. However, a number of challenges have nonetheless been encountered in bringing about the optimal benefits of the currently available therapeutics of AIDS and HIV-1 infection to individuals receiving HAART. They include (i) drug-related toxicities; (ii) partial restoration of immunologic functions once individuals developed AIDS; (iii) development of various cancers as a consequence of survival prolongation; (iv) flame-up of inflammation in individuals receiving HAART or immune re-construction syndrome (IRS); and (v) increased cost of antiviral therapy. Such limitations of HAART are exacerbated by the development of drug-resistant HIV-1 variants.
Efforts to counter the development of resistance with new compounds have been recently reported (Ghosh A K, et al., Bioorg. Med. Chem. Lett. 1998; Ghosh A K, et al., Farmaco 2001; Ghosh A K, et al., ChemMedChem, 2006; Yoshimura K, et al., J. Virol. 2002; Koh Y, Nakata H, Maeda K., Antimicrob Agents Chemother, 2003). The FDA approved Darunavir on Jun. 23, 2006; on Oct. 21, 2008, FDA granted traditional approval to Prezista (darunavir), co-administered with ritonavir and with other antiretroviral agents, for the treatment of HIV-1 infection in treatment-experienced adult patients. In addition to the traditional approval, a new dosing regimen for treatment-naïve patients was approved (Tie Y, et al., Proteins 2007; Kovalevsky A Y, et al., J. Med. Chem. 2006; Ghosh A K, Chapsal B D, Weber I T, Mitsuya H., Acc. Chem. Res. 2008-; Ghosh A K, et al., J. Med. Chem. 2006; Ghosh A K, et al., J. Med. Chem. 2009; Ghosh A K, Chen Y., Tetrahedron Lett., 1995). One of the PIs, darunavir (DRV), was first approved for HIV/AIDS patients harboring drug-resistant HIV that do not respond to other antiretroviral drugs. Recently, DRV has received full approval for all HIV/AIDS patients including children infected with HIV-1. DRV incorporates a stereochemically defined fused bis-tetrahydrofuran (bis-THF) as the P2-ligand. Each of the documents cited herein is incorporated herein by reference. Inhibition of HIV-1 protease has been documented as an effective strategy for the treatment of HIV/AIDS.
Herein described are potent inhibitors of HIV protease, including against various multidrug-resistant HIV-1 variants. In one embodiment, inhibitors described herein show nearly a 10-fold inhibition improvement over Darunavir (DRV). In another embodiment, inhibitors described herein also potently block protease dimerization by at least a factor of 10-fold compared to DRV.
The invention described herein includes novel compounds and compositions for treating patients in need of relief from HIV, AIDS, and AIDS-related diseases. In addition, the invention described herein includes methods for treating HIV, AIDS, and AIDS-related diseases using the compounds described herein as well as known compounds that heretofore have not been used or described as being useful in the treatment of such diseases.
In an embodiment of the invention, a compound having the formula
or a pharmaceutically acceptable salt, isomer, mixture of isomers, crystalline form, non crystalline form, hydrate, or solvate thereof; wherein
X1 is a bond or optionally substituted alkylene;
X2 is a bond, C(O), S(O), S(O)2, optionally substituted amino, or optionally substituted alkylene;
R1 and R2 are in each instance independently selected from the group consisting of hydrogen, P(O)(OR)2 and a prodrug forming group, where R is independently selected in each instance from hydrogen or alkyl;
R3 is sulfonyl, acyl, amino, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted;
R4 is hydrogen, halogen, —OH, or —NO2, or R4 is amino, alkoxyl, sulfonyl, acyl, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl, each of which is optionally substituted; or R3, R4, X2 and the attached nitrogen form an optionally substituted heterocyclyl;
R5 and R6 are independently in each instance hydrogen or selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
Z is
wherein * indicates the point of attachment; m is 0, 1, or 2;
W1 and W2 are in each instance independently selected from the group consisting of optionally substituted alkylene, alkyleneoxy, alkyleneamino, alkylenethio, alkylenesulfoxyl, and alkylenesulfonyl;
W3 and W4 are in each instance independently selected from the group consisting of amino, oxygen, alkylene, alkyleneoxy, alkyleneamino, and heteroalkylene, wherein at least one of W1 or W2 is oxygen, and wherein when one of W1 or W2 is optionally substituted methylene, at least one of W3 or W4 is oxygen or alkyleneoxy, and wherein Z does not include a peroxide bond, a sulfenate bond, or a sulfenamide bond;
X3 is a bond or optionally substituted methylene; and
Y is hydrogen, hydroxyl, or carbonyl, or amino, acyl, sulfonyl, alkyl, or heteroalkyl, each of which is optionally substituted is described.
In another embodiment
or a pharmaceutically acceptable salt, isomer, mixture of isomers, crystalline form, non crystalline form, hydrate, or solvate thereof; wherein
X1 is a bond or optionally substituted alkylene;
X2 is a bond, C(O), S(O), S(O)2, optionally substituted amino, or optionally substituted alkylene;
R1 and R2 are in each instance independently selected from the group consisting of hydrogen, P(O )(OR)2 and a prodrug forming group, where R is independently selected in each instance from hydrogen or alkyl;
R3 is sulfonyl, acyl, amino, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted;
R4 is hydrogen, halogen, —OH, or —NO2, or R4 is amino, alkoxyl, sulfonyl, acyl, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl, each of which is optionally substituted; or R3, R4, X2 and the attached nitrogen form an optionally substituted heterocyclyl;
R5 and R6 are independently in each instance hydrogen or selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
Z is

wherein * indicates the point of attachment; n is 1, 2, or 3;
W1 and W2 are in each instance independently selected from the group consisting of optionally substituted methylene, oxygen, and amino;
W3 and W4 are in each instance independently selected from the group consisting of amino, oxygen, alkylene, and heteroalkylene, wherein at least one of W1 or W2 is oxygen, and wherein when one of W1 or W2 is optionally substituted methylene, at least one of W3 or W4 is oxygen, and wherein Z does not include a peroxide bond, a sulfenate bond, or a sulfenamide bond;
X3 is a bond or optionally substituted methylene; and
Y is hydrogen, hydroxyl, or carbonyl, or amino, acyl, sulfonyl, alkyl, or heteroalkyl, each of which is optionally substituted is described.
In another embodiment, a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds described herein for treating HIV infection is described.
In another embodiment, compounds described are used in the treatment of HIV, AIDS, and AIDS-related diseases. Also described herein is a method for treating a patient in need of relieve of an HIV infection, the method comprising the step of administering to a patient in need of relief from the HIV infection a therapeutically effective amount of one or more compounds of any of the compounds or the compositions described herein.
In another embodiment, described herein is the synthesis of a series of inhibitors for HIV-1 protease that incorporate conformationally constrained and stereochemically defined tris-tetrahydrofuran derivatives as the P2-ligands. These inhibitors have shown marked enzyme-inhibitory and antiviral potency. A number of these inhibitors are very potent against multi-drug resistant HIV-1 variants.